We are investigating the role of cAMP signaling downstream of G alpha s heterotrimeric proteins in the development and progression of different cancers, including non-melanoma skin cancer and prostate cancer. By altering the activation of this pathway in human cancer cells and animal models we are dissecting the mechanisms by which this pathway can act both as in tumor suppressor and promotion. We have found that protein kinas A inhibitor proteins (PKI), which regulate the kinase activity of PKA, can influence the signaling pathways downstream of cAMP signaling. PKI proteins can increase activation of mitogenic signaling pathways in cells and we have found that genomic alterations in PKI genes are observed in numerous human cancers, suggesting that dysregulation of PKI protein expression can have a role in pathological conditions. We are currently studying the effects of altered expression of these proteins in cancer using cellular and animal models. We are also investigating the potential of targeting G alpha s and PKA for skin cancer treatment, particularly for basal cell carcinoma (BCC). We have demonstrated that inactivation of G alpha s and PKA leads to BCC formation. We are now testing the hypothesis that increasing cAMP and PKA signaling might be a target for reducing BCC proliferation. We have treated animal and cellular models of BCC with compounds that alter PKA activity, phosphodiesterase (PDE) inhibitors. PDE inhibitors treatments do not show an effect in BCC growth or initiation, indicating that they might not be a good target for treatment in this cancer. We are currently investigating targeting other components G alpha s and PKA pathway, including EPACs (exchange proteins directly activated by cAMP), for BCC treatment.